Stephen C. Piscitelli, PharmD


May 12, 2000


Is it necessary to increase the dose of efavirenz (from 600-800 mg) when given in combination with rifampin?

Lidiette Salas, PharmD

Response from Stephen C. Piscitelli, PharmD

Drug-drug interactions involving efavirenz can be very complicated, because this agent possesses both inhibitory and inducing effects on the 3A4 isoform of the cytochrome P450 system. For example, efavirenz modestly increases the area under the curve (AUC) of ritonavir and nelfinavir but reduces the AUC of indinavir by approximately 30%, necessitating a dosage increase in indinavir.[1]

In terms of the changes in efavirenz concentrations by other drugs, efavirenz AUC is generally not markedly changed by CYP3A4 inducers or inhibitors. Ritonavir increases efavirenz AUC by only 21%, compared with 3- to 5-fold increases in concomitant protease inhibitors by ritonavir. Clarithromycin, nelfinavir, and indinavir do not appreciably affect the AUC of efavirenz.[1,2]

Rifampin is one of the most potent inducers of the CYP450 system. The addition of rifampin can decrease concentrations of saquinavir and indinavir by over 80%.[3] However, a study in healthy volunteers demonstrated that rifampin has only a modest effect on efavirenz AUC. Twelve healthy volunteers received 400 mg per day of efavirenz for 7 days followed by 600 mg of rifampin for 7 days. Pharmacokinetic sampling was performed on day 7 and 14 for efavirenz concentrations. The AUC of efavirenz was reduced by a mean of 26% by rifampin compared with efavirenz alone.[4]

Based on this study, no dose adjustment of rifampin was deemed necessary. However, the Centers for Disease Control and Prevention's recent update on rifamycin use in HIV-infected patients states that some experts recommend increasing the efavirenz dose to 800 mg per day.[5] The fact remains that there is no clinical experience with this combination to date, although the available pharmacokinetic data suggest efavirenz dosing does not need adjustment with concomitant rifampin.